The Connection Between A-T and Breast Cancer

In fact, women who carry the A-T gene have a 35 to 40 percent risk of breast cancer. The New England Journal of Medicine has reported that as many as one of every eight women with breast cancer is a carrier of the A-T gene. Carriers of the A-T gene are also sensitive to physical damage from small amounts of radiation, such as X-rays.

Heterozygote Risk Debate   

Unedited Information from Researchers on A-T and the Heterozygote Breast Cancer Risk Question:

1. 9-4-98 from Dr. Harold Lederman:

The most recent data suggests that A-T carriers are NOT at significantly increased risk for breast cancer compared to the rest of the population. As such, the decision to use tamoxifen should depend primarily on whether or not there is a family history of breast cancer.

Dr. H Lederman
A-T Clinical Center
Johns Hopkins

2. 9-4-98 from Dr. Michael Swift:

Readers of Dr. Howard Lederman's September 4 posting may, mistakenly, believe that "... that A-T carriers are NOT at significantly increased risk of breast cancer." It would be a terrible outcome if this statement led female A-T carriers to ignore their elevated risk of breast cancer. The data showing that female A-T carriers have excess breast cancers meet the highest scientific standards. There were full reports in the New England Journal of Medicine in 1987 and 1991. The fact that the A-T gene predisposes carrier women to breast cancer was confirmed rigorously in 1996 using a reliable molecular method for determining who carries this gene in A-T families. In contrast to what Dr. Leonard said, the statistics in these studies were excellent. Did he even read these studies? On average, the risk of breast cancer for A-T heterozygotes is about four-fold that of non-carriers.

In contrast, there are major technical problems with all the inconclusive studies referred to by Dr. Lederman and Dr. Leonard. Most are unpublished. One group published two studies contradicting each other. All studies were too small to meet standard statistical criteria. All used unreliable methods for finding A-T gene carriers. None of them met a high enough standard to be convincing.

It is difficult to understand preferring studies of limited value over solid rigorous studies on the same topic. The issue is not purely academic, since female A-T carriers may be harmed by incorrect information about their risk of breast cancer. There is a long unfortunate history of opposition by "scientists" to rigorous new scientific findings, even if this opposition leads to many unnecessary illnesses or deaths. Among the many famous examples is the story of Semmelweis, who discovered that washing his hands between deliveries cut the rate of childbirth fever by 95%. French doctors refused for thirty years to listen to his data - hundreds of thousands of death resulted.

Our newest, as yet unpublished, data continue to confirm that female A-T carriers have an excess risk of breast cancer. We also continue to hear about new breast cancers that have arisen in female A-T patients in their 30s or late 20s. In our current research we plan to determine the types of breast cancers found in A-T carriers, the responses to treatment, and the factors influencing survival. No data are yet available to determine how valuable tamoxifin is in preventing breast cancer in A-T carriers. Perhaps a clinical trial could be organized. We welcome your suggestions or questions.

Michael Swift, MD
The Institute for the Genetic Analysis of Common Diseases
New York Medical College
4 Skyline Drive
Hawthorne, New York 10532
USA
Phone 914 347 2592
Fax 914 592 2275
michael_swift@nymc.edu

British Medical Journal 1998;317:486-487 ( 22 August )
Editorials
Role of the ataxia-telangiectasia gene (ATM) in breast cancer

A-T heterozygotes seem to have an increased risk but its size is unknown Genetic predisposition accounts for 5-10% of breast cancer, and two genesBRCA1 and BRCA2 have attracted most attention as high risk factors.1 However, these two genes probably account for only a small proportion of the genetic risk while other more common but less penetrant genes may explain the remainder of genetically predisposed breast cancers.2 One such candidate is the gene, ATM, mutated in the human genetic disorder ataxia-telangiectasia (A-T).3 A-T heterozygotes (estimated to be 1% of the population) do not show any of the major symptoms of the disease, though there is good evidence that they have an underlying cellular radiosensitivity, but to a lesser extent than observed in A-T homozygotes.4 These observations, together with earlier epidemiological studies, reveal a raised incidence of mortality from cancer among blood relations of patients with ataxia-telangiectasia, with the greatest relative risk for breast cancer (5.1) in female relatives of patients.5

An association between the incidence of breast cancer and A-T heterozygosity was also revealed in two separate but smaller studies. 6 7 Based on an independent assessment of all these data the relative risk of breast cancer in A-T heterozygotes was estimated to be 3.9, with A-T carriers representing 3.8% of all cases.8 With knowledge of the sequence of the ATM gene, Fitzgerald et al detected heterozygous mutations in 2/202 (1%) healthy women with no personal history of cancer.9 The frequency of 1% is consistent with that predicted from epidemiological studies.5

When patients with early onset breast cancer (>40 years) were screened 2/410 (0.5%) showed mutations in the ATM gene. Fitzgerald et al therefore concluded that "heterozygous ATM mutations do not confer genetic predisposition to early onset breast cancer." On the other hand, a recent study by Athma et al using molecular genotyping suggested that A-T heterozygotes are predisposed to breast cancer.10

Among 33 women with breast cancer 25 were A-T heterozygotes compared with an expected 15. For patients with earlier onset disease (<60 years) the odds ratio was 2.9 (21 cases), while for older patients it was 6.4 (12 cases) Based on these relative risks the authors calculated that 6.6% of all cases of breast cancer in America occur in A-T heterozygotes. Clearly these two studies appear to be in conflict. In an analysis of these data Bishop and Hoppe pointed out that precise estimates were difficult since the study of Fitzgerald et al relied on a small number of mutations while that of Athma et al analysed only a small number of breast cancers.11 Larger scale studies are required with emphasis on age of onset of breast cancer to address conclusively the potential association between mutations in ATM and risk of developing breast cancer. In a workshop last November in Clermont-Ferrand results were presented from studies in several countries, but the connection between A-T heterozygosity and breast cancer remains unresolved.

If a link between breast cancer and A-T heterozygosity is established, what are the clinical implications? As for any gene that increases the risk of breast cancer, A-T carriers should ideally be identified, but given the size of the ATM cDNA (9.168 kb) and the known distribution of mutations over the entire length of the cDNA it would be difficult and expensive to conduct general population screening. Relying on identifying carriers in A-T families would narrow the scope and usefulness of such screening. A-T carriers would need to be identified by some other characteristic. One such feature does existcellular radiosensitivity but it is not amenable to a widespread screening assay.

This intermediate radiosensitivity does, however, raise another issue which is pertinent to the development of breast cancer. Swift et al concluded that diagnostic or occupational exposure to ionising radiation probably increases the risk of breast cancer in women heterozygous for A-T.5 High doses of ionising radiation, particularly before puberty, are known to increase the risk of breast cancer. What has emerged as a contentious issue is whether mammography screening leads to an increased risk for A-T carriers. A well conducted mammographic examination involves an absorbed dose of about 0.3 cGy/breast, which if applied annually over 35 years (40-75 years) would give rise to a lifetime radiation dose of 10.5 cGyapproximately the same as background radiation.12 Exposures of this order, at the age of 40, are estimated to increase the number of deaths from breast cancer by about 1/2000 women, which is insignificant compared with the natural lifetime risk of 1/9 for breast cancer.

What then of carriers of the A-T gene? A-T heterozygotes are intermediate in cellular sensitivity to radiation between controls and A-T patientst hat is, at best 1.5-fold to twofold more sensitive than controls. Thus a total dose of 10.5 cGy would not be expected to increase significantly the lifetime risk for breast cancer in A-T carriers.

For A-T carriers the picture that emerges is that while epidemiological studies point to a threefold to fourfold increased risk for breast cancer there remains uncertainty whether this is supported by mutation analysis of the ATM gene. Screening of increased numbers of patients with breast cancer is required to support a small moderate increased relative risk for A-T heterozygotes. It seems unlikely that the intermediate cellular radiosensitivity in A-T carriers increases the risk of breast cancer during mammographic screening, at least when this procedure is restricted to women aged over 40.

Martin Lavin, Professor of molecular oncology.
Queensland Institute of Medical Research/Department of Surgery, University of
Queensland, Brisbane, Queensland 4029, Australia

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7.Borresen AL, Anderson TI, Tretli S, Heiberg A, Moller P. Breast cancer and other cancers in Norwegian families with ataxia-telangiectasia. Genes Chrom Cancer 1990; 2: 339-340[Medline].

8.Easton D. Cancer risks in A-T heterozygotes. Int J Radiat Biol 1994; 66: S177-S182[Medline].

9.Fitzgerald MG, Bean JM, Hegde SR, Unsal H, MacDonald DJ, Harkin DP, et al. Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nature Genet 1997; 15: 307-310[Medline].

10.Athma P, Rappaport R, Swift M. Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer. Cancer Genet Cytogenet 1996; 92: 130-134[Medline].

11.Bishop DT, Hopper J. AT-tributable risks? Nature Genet 1997; 15: 226[Medline].

12.Norman A, Withers HR. Mammography screening for A-T heterozygotes. In: Gatti RA, Painter RB, eds. Ataxia-telangiectasia. Berlin: Springer, 1993:137-140.